Abstract

Acquired resistance to therapy is a major obstacle in clinical oncology, and little is known about the contributing mechanisms of the host response to therapy. Here we show that the pro-inflammatory cytokine, IL-1β, is overexpressed in response to paclitaxel chemotherapy in macrophages, subsequently promoting the invasive properties of malignant cells. In accordance, blocking IL-1β, or its receptor, using either genetic or pharmacologic approach, results in slightly retardation of primary tumor growth; however, it accelerates metastasis spread. Tumors from mice treated with combined therapy of paclitaxel and the IL-1 receptor antagonist, Anakinra, exhibit increased number of M2 macrophages and vessel leakiness when compared to paclitaxel monotherapy treated mice, indicating a pro-metastatic role of M2 macrophages in the IL-1β-deprived microenvironment. Taken together, these findings demonstrate the dual effects of blocking the IL-1 pathway on tumor growth. Accordingly, treatments using 'add-on' drugs to conventional therapy should be investigated in appropriate tumor models consisting of primary tumors and their metastases.